The invention relates generally to oxazolone derivatives, and pharmaceutically acceptable salts or solvates thereof, which exhibit useful pharmacological properties. In particular, the invention relates to compounds, pharmaceutical compositions and methods of using oxazolone derivatives as alpha1-adrenergic receptor (alpha1-adrenoceptor) modulators, preferably antagonists.
Alpha1-adrenergic receptors are G-protein coupled transmembrane receptors that mediate various actions of the sympathetic nervous system through the binding of the catecholamines, epinephrine and norepinephrine. Currently, several subtypes of the alpha1-adrenergic receptors are known to exist for which the genes have been cloned: alpha1A (previously known as alpha1C), alpha1B and alpha1D. The existence of an additional subtype, the alpha1L-adrenergic receptor subtype, has been proposed; however, the gene for the alpha1L-adrenergic receptor subtype has yet to be cloned. Although these subtypes can be pharmacologically distinguished, existing subtype-selective compounds are only moderately specific and may interact with more than one alpha1-adrenergic receptor subtype. Accordingly, therapeutic use of nonselective alpha1-adrenergic receptor antagonists must be carefully monitored as such antagonists can produce significant undesirable side effects such as postural hypotension, sedation or depression, increased gastrointestinal motility and diarrhea, impaired ability to ejaculate, nasal stuffiness, akinesia and the like.
Non-selective alpha1-adrenoceptor antagonists have been used to treat lower urinary tract symptoms associated with benign prostatic hyperplasia (BPH). Further, alpha1-adrenoceptor antagonists can be effective in reducing or alleviating urinary tract disorders and/or the symptoms thereof, such as pelvic hypersensitivity, overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, incontinence, urge incontinence, urethritis, prostatodynia, idiopathic bladder hypersensitivity, and the like.
Compounds that interact more selectively with a particular alpha1-adrenergic receptor subtype may prove clinically useful in providing more selective treatment of conditions and diseases, and symptoms thereof, associated with activity at the receptor subtype. For example, alpha1-adrenergic receptor antagonists that can selectively reduce or alleviate urinary tract disorders or symptoms, or ameliorate nociceptive and/or neurogenic pain without affecting blood pressure or causing postural hypotension, are desirable. Presently available alpha1-adrenergic antagonists are either relatively nonselective with respect to the subtypes with which they interact or generally are not selective for the alpha1B-adrenergic receptor subtype.
U.S. Pat. No. 5,736,412 (Zambias et al.) refers to a method of generating a plurality of certain chemical compounds in a spatially arranged array.
U.S. Pat. No. 5,962,736 ( Zambias et al.) refers to logically ordered arrays of compounds and methods of making and using the same.
U.S. Pat. No. 5,859,014 (Bantle et al.) refers to certain pyrimidinedione, pyrimidinetrione, triazinedione and tetrahydroquinazolinedione derivatives which are disclosed as being useful as alpha1 adrenergic receptor antagonists.
PCT Published Application WO 95/17903 (assigned to Arqule) refers to a modular design and synthesis of oxazolone-derived molecules.
PCT Published Application WO 95/25726 (assigned to Recordati) refers to certain quinazolyl-amino derivatives which are disclosed as having alpha antagonist activity.
PCT Published Application WO 98/46551 (assigned to Arqule) refers to a synthesis and use of certain biased arrays.
PCT Published Application WO 98/46559 (assigned to Arqule) refers to a synthesis and use of certain alpha-ketoamide derivatives and arrays.
PCT Published Application WO 98/56028 (assigned to Arqule) refers to an automated, highthroughput method for screening a plurality of compounds using mass spectrometry.
PCT Published Application WO 96/16049 (assigned to Glaxo) refers to certain oxazoles as alpha-1C antagonists.
PCT Published Applications WO 99/09979, WO 99/09980, and WO 99/09829 (all assigned to Eli Lilly) refer to certain oxazoles for treating neuropathic pain.
European Patent Application EP 602851 refers to certain quinazoline derivatives.
German Patent Publications No. 117 224, 117 225, 117 228, and DE 2 659 543 refer to synthesis of certain oxazolinones.
Japanese Patent Application No 08-27132 refers to the preparation of certain oxazolones.
Giardina et al., J. Med. Chem. 1996, 39, 4602-4607 refer to the synthesis of cyclazosin enantiomers and their activity as alpha-1B antagonists.
Patane et al., J. Med. Chem 1998, 41, 1206-1208 refer to L-765314 as a potent and selective alpha-1B antagonist.
Xie et al., Soc. for Neuroscience Abstract 24, 2089(1998) refer to certain alpha 1B adrenergic receptor mRNA expression in rat DRG after spinal nerve injury.
Lee et al, J. Neurophysiol. 81, 2226-2233 (1999) refer to certain receptor subtypes mediating the adrenergic sensitivity of pain behaviour.
The present invention addresses the aforementioned needs in the art by providing oxazolone derivatives, and pharmaceutically acceptable salts or solvates thereof, which exhibit useful pharmacological properties. Particularly, the present invention relates to oxazolone derivatives, pharmaceutical compositions thereof and methods of using such derivatives as alpha1-adrenergic receptor (alpha1-adrenoceptor) modulators, preferably antagonists.
In one embodiment, the invention relates to a compound comprising the Formula (I): 
wherein:
X is Formula (A), (B) or (C); 
m is an integer ranging from 1 to 6 inclusive;
n is an integer ranging from 0 to 5 inclusive;
p, q, r and s are each independently integers ranging from 1 to 3
inclusive, with the proviso that when p is greater than one, r is 1 and
when s is greater than one, q is 1;
Y is xe2x80x94(CH2)wxe2x80x94R3, xe2x80x94(CH2)wxe2x80x94COxe2x80x94R4, xe2x80x94(CH2)wxe2x80x94COxe2x80x94NHxe2x80x94R5, xe2x80x94(CH2)wxe2x80x94C(NR6)xe2x80x94NHxe2x80x94R7, xe2x80x94(CH2)wxe2x80x94SO2xe2x80x94R8, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94R9, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94R10, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R11, or xe2x80x94(CH2)wxe2x80x94NHxe2x80x94SO2xe2x80x94R12; wherein w is an integer ranging from 0 to 3 inclusive;
Z is CH or N;
R1 is cycloalkyl, cycloalkenyl, heterocyclic, aryl or heteroaryl;
R2a, R2b or R2c are each independently in each occurrence hydrogen, alkyl, alkenyl, cycloalkyl, aryl, or arylalkyl; or R2a and R2b taken together with the carbons to which they are attached form a 5- to 7-membered ring structure;
R3 is heterocyclic or heteroaryl;
R4, R5, R8, R9, R10, R11 and R12 are each independently in each occurrence hydrogen, alkyl, alkoxy, hydroxyalkyl, alkylthio, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
R6 and R7 are each independently in each occurrence hydrogen, alkyl, hydroxyalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclic, heterocyclicalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl;
or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, X is: 
or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a more preferred embodiment, X is piperazinyl or piperidinyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. Even more preferably X is piperazinyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In a preferred embodiment, Y is xe2x80x94(CH2)wxe2x80x94R3, xe2x80x94(CH2)wxe2x80x94COxe2x80x94R4, xe2x80x94(CH2)wxe2x80x94COxe2x80x94NHxe2x80x94R5, xe2x80x94(CH2)wxe2x80x94C(NR6)xe2x80x94NHxe2x80x94R7, xe2x80x94(CH2)wxe2x80x94SO2xe2x80x94R8, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94R9, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94R10, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R11, or xe2x80x94(CH2)wxe2x80x94Hxe2x80x94SO2xe2x80x94R12; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, Y is xe2x80x94(CH2)wxe2x80x94COxe2x80x94R4, xe2x80x94(CH2)wxe2x80x94SO2xe2x80x94R8, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94R9, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94R10, xe2x80x94(CH2)wxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R11, or xe2x80x94(CH2)wxe2x80x94NHxe2x80x94SO2xe2x80x94R12; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, Y is xe2x80x94(CH2)wxe2x80x94R3; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, Y is xe2x80x94(CH2)wxe2x80x94xe2x80x94COxe2x80x94NHxe2x80x94R5; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, Y is xe2x80x94(CH2)wxe2x80x94C(NR6)xe2x80x94NHxe2x80x94R7; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R1 is aryl or heteroaryl; more preferably R1 is an alkyl-, halo- or alkoxy-substituted phenyl, a bicyclic aryl or a bicyclic heteroaryl; and even more preferably R1 is a 3-substituted phenyl (e.g., 3-methylphenyl, 3-chlorophenyl, 3-methoxyphenyl), naphthyl, fluoronaphthyl, thianaphthenyl(benzothiophenyl), benzofuranyl, quinolinyl, indolyl, fluorobenzofuranyl, or benzimidazolyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R3 is a moiety selected from benzooxazolyl, pyrazolyl, pyrimidyl, pyrrolyl, quinolinyl, isoquinolinyl, benzoisoquinolinyl dione, indolyl, imidazolyl, benzimidazolyl, imidazopyridinyl, oxazolyl, isooxazolyl, quinoxanilyl, thiazolyl, benzothiazolyl, or thiazolidinyl; wherein the moiety is optionally substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, cycloalkyl, cycloalkylenyl, heterocyclic, aryl or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R4 is is alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R5 is alkyl, cycloalkyl, heterocyclicalkyl, aryl, arylalkyl, or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R6 is hydrogen or alkyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R7 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R8 is alkyl, aryl, arylalkyl, or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R9 is alkyl, arylalkyl, or heteroarylalkyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R10 is alkyl, alkoxy, cycloalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R11 is alkyl, cycloalkyl, heterocyclicalkyl, aryl, arylalkyl, or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In another preferred embodiment, R12 is alkyl, aryl, arylalkyl, or heteroaryl; or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.
In an additional embodiment, the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula (I), or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof as described herein. In another embodiment, at least one compound of Formula (I), or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof as described herein, is an alpha1-adrenoceptor modulator. In a preferred embodiment at least one compound is an alpha1-adrenoceptor antagonist. In a more preferred embodiment, at least one compound of Formula (I), or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof as described herein is an alpha1B-adrenoceptor antagonist.
In another embodiment, the invention relates to a method of treating a disease state alleviable by treatment with an alpha1-adrenoceptor modulator. In a preferred embodiment, the invention relates to a method of treating a disease state alleviable by treatment with an alpha1-adrenoceptor antagonist, such as disease states of the urinary tract such as incontinence, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity (including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like), urge incontinence, urethritis, or idiopathic bladder hypersensitivity; male erectile dysfunction and female sexual dysfunction; pain including acute pain, inflammatory pain, neuropathic pain and complex regional pain syndromes; hypertension and cardiac dysfunctions resulting from altered contractility, and/or hypertrophy.
In a preferred embodiment, the disease state comprises disorders of the urinary tract, preferably the disease state is incontinence, benign prostatic hypertrophy, prostatitis, detrusor hyperreflexia, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis or idiopathic bladder hypersensitivity.
In a preferred embodiment, the disease state is male erectile dysfunction or female sexual dysfunction.
In another preferred embodiment, the disease state is pain, preferably inflammatory pain, neuropathic pain, cancer pain, acute pain, chronic pain or complex regional pain syndromes.
In an additional embodiment, the invention relates to a method of treating a subject which comprises administering to the subject a therapeutically effective amount of at least one compound of Formula (I), or individual isomers or racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof as described herein or a pharmaceutical composition thereof as described herein. In a preferred embodiment, the subject has a disease state alleviable by treatment with an alpha1-subtype adrenoceptor modulator, preferably an antagonist, more preferably an alpha1B-adrenoceptor antagonist.
These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein.
The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Remington""s Pharmaceutical Sciences, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.); Textbook of Pain (P. D. Wall and R. Melzack, editors, Third Edition, Churchill Livingstone, 1994); Fieser and Fieser""s Reagents for Organic Synthesis, Wiley and Sons, New York, 1991, Volumes 1-15; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons, New York, 1991, Volumes 1-40.
All publications, patents and patent applications cited herein, whether supra or infra, are hereby each incorporated by reference in their entirety.
As used in this specification and the appended claims, the singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include singular and plural references unless the content clearly dictates otherwise. Thus, for example, reference to xe2x80x9can antagonistxe2x80x9d may include a mixture of two or more such agents.
I. Definitions
In describing the present invention, the following terms will be employed, and are intended to be defined as indicated below.
xe2x80x9cAlkylxe2x80x9d means the monovalent linear or branched saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from one to twelve carbon atoms inclusive, unless otherwise indicated. Examples of an alkyl radical include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
xe2x80x9cLower alkylxe2x80x9d means the monovalent alkyl radical as defined herein, having from one to six carbon atoms inclusive, unless otherwise indicated. Examples of a lower alkyl radical include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, n-hexyl and the like.
xe2x80x9cAlkylenexe2x80x9d means the divalent linear or branched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to six carbons inclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl-propylene, butylene, 2-ethylbutylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means the monovalent linear or branched unsaturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing a double bond and having from two to six carbon atoms inclusive, unless otherwise indicated. Examples of an alkenyl radical include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-butenyl, and the like.
xe2x80x9cAlkynylxe2x80x9d means the monovalent linear or branched unsaturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, containing a triple bond and having from two to six carbon atoms inclusive, unless otherwise indicated. Examples of an alkynyl radical include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d means the radical xe2x80x94Oxe2x80x94R, wherein R is a lower alkyl radical as defined herein. Examples of an alkoxy radical include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
xe2x80x9cAlkoxycarbonylxe2x80x9d means the radical Rxe2x80x94Oxe2x80x94C(O)xe2x80x94, wherein R is a lower alkyl radical as defined herein. Examples of an alkoxycarbonyl radical include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, sec-butoxycarbonyl, and the like.
xe2x80x9cAcyloxyxe2x80x9d means the radical xe2x80x94OC(O)R, wherein R is a lower alkyl radical as defined herein. Examples of acyloxy radicals include, but are not limited to, acetoxy, propionyloxy, and the like.
xe2x80x9cAcylxe2x80x9d or xe2x80x9calkanoylxe2x80x9d means the radical xe2x80x94C(O)xe2x80x94R wherein R is a lower alkyl as defined herein. Examples of acyl radicals include, but are not limited to, formyl, acetyl, propionyl, butyryl, and the like.
xe2x80x9cAlkylaminoxe2x80x9d means the radical xe2x80x94NHR, wherein R is a lower alkyl radical as defined herein. Examples of alkylamino radicals include, but are not limited to, methylamino, (1-ethylethyl)amino, and the like.
xe2x80x9cAminoalkylxe2x80x9d means the radical xe2x80x94RNRxe2x80x2Rxe2x80x3, wherein R is a lower alkyl radical as defined herein, and Rxe2x80x2 and Rxe2x80x3 are each independently H or a lower alkyl radical as defined herein. Examples of aminoalkyl radicals include, but are not limited to, aminomethyl, aminoethyl, aminopropyl, and the like.
xe2x80x9cAlkylthioxe2x80x9d means the radical xe2x80x94SR, wherein R is a lower alkyl radical as defined herein. Examples of alkylthio radicals include, but are not limited to, methylthio, butylthio, and the like.
xe2x80x9cDialkylaminoxe2x80x9d means the radical xe2x80x94NRxe2x80x2Rxe2x80x3, wherein Rxe2x80x2 and Rxe2x80x3 are each independently lower alkyl radicals as defined herein. Examples of dialkylamino radicals include, but are not limited to, dimethylamino, methylethylamino, diethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cArylxe2x80x9d means the monovalent monocyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino, unless otherwise indicated. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, diphenylmethyl, 9H-fluorenyl, indanyl, anthraquinolyl, and the like.
xe2x80x9cHeteroarylxe2x80x9d means the monovalent aromatic carbocyclic radical having one or more rings incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, or sulfur) which can optionally be substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino, unless otherwise indicated. Examples of heteroaryl radicals include, but are not limited to, naphtyridinyl, anthranilyl, benzooxazolyl, pyridyl, pyrrolyl, pyrazolyl, pyrazinyl, pyrimidyl, thiophenyl, furanyl, benzofuranyl, dihydrobenzofuranyl, 3,3-dimethyl-2,3-dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, tetrahydroquinoxalinyl, benzodioxazolyl, benzoisoquinolinyl dione, benzodioxanyl, indolyl, 2,3-dihydroindolyl, thianaphthenyl, dihydrothianaphthenyl, imidazolyl, benzoimidazolyl, benzimidazolyl, azabenzimidazolyl, oxazolyl, isooxazolyl, quinoxalinyl, thiazolyl, benzothiazolyl, thiazolidinyl, pyranyl, tetrahydropyranyl pyranyl, benzo[1,3]dioxolyl, 2,3-dihydrobenzo[1,4]dioxinyl, thienyl, benzo[b]thienyl, 1,2,3,4-tetrahydro[1,5]naphthyridinyl, 2H-3,4-dihydrobenzo[1,4]oxazine, 4,5-dihydro-1H-imidazol-2-yl, and the like.
xe2x80x9cArylalkylxe2x80x9d means the radical Rxe2x80x2Rxe2x80x3xe2x80x94, wherein Rxe2x80x2 is an aryl or heteroaryl radical as defined herein, and Rxe2x80x3 is an alkyl radical as defined herein. Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.
xe2x80x9cCycloalkylxe2x80x9d means the monovalent saturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino, unless otherwise indicated. Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, hydrogenated derivatives of aryl as defined herein, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means the radical Rxe2x80x2Rxe2x80x3xe2x80x94, wherein Rxe2x80x2 is a cycloalkyl radical as defined herein and Rxe2x80x3 is an alkyl radical as defined herein. Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, 3-ethylcyclobutyl, cyclopentylethyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d means the monovalent unsaturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino, unless otherwise indicated. Examples of cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, hydrogenated derivatives of aryl as defined herein, and the like.
xe2x80x9cHeterocyclylxe2x80x9d means the monovalent saturated carbocyclic radical, consisting of one or more rings, incorporating one, two or three heteroatoms (chosen from nitrogen, oxygen or sulfur), which can optionally be substituted with one or more of the following substituents: hydroxy, cyano, alkyl, alkoxy, thioalkyl, halo, haloalkyl, trifluoromethyl, hydroxyalkyl, alkoxycarbonyl, nitro, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl and sulfonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, imidazolidinyl, pyrrolidinyl, pyrrolidin-2-one, pyrrolidin-2,3-dione, hydrogenated derivatives of heteroaryl as defined herein, and the like.
xe2x80x9cHeterocycloalkylxe2x80x9d means the radical of the formula Rxe2x80x2Rxe2x80x3, where Rxe2x80x2 is a heterocyclic radical as defined herein and Rxe2x80x3 is an alkylene radical as defined herein. Examples of heterocycloalkyl radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like.
xe2x80x9cHalogenxe2x80x9d means the radical fluoro, chloro, bromo, and iodo.
xe2x80x9cHaloalkylxe2x80x9d means the lower alkyl radical as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of haloalkyl radicals include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means the lower alkyl radical as defined herein, substituted with one or more hydroxy groups. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, the phrase xe2x80x9cwhich group is optionally substituted with one to three halo atomsxe2x80x9d or xe2x80x9coptionally substituted arylxe2x80x9d means that the group referred to may or may not be substituted in order to fall within the scope of the invention, and that the description includes both substituted and unsubstituted moieties.
xe2x80x9cProtectedxe2x80x9d in reference to a compound or a group means the derivative of compound or group in which a reactive site or sites are blocked with protective groups.
xe2x80x9cProtective groupxe2x80x9d or xe2x80x9cprotecting groupxe2x80x9d means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotective reactive site and which can be readily removed after the selective reaction is completed. Certain processes may rely upon the protective groups to block reactive oxygen or nitrogen atoms present in the reactants. Acceptable protective groups for alcoholic or phenolic hydroxyl groups, which may be removed successively and selectively includes groups protected as acetates, haloalkyl carbonates, benzyl ethers, alkylsilyl ethers, heterocyclic ethers, and methyl or alkyl ethers, and the like. Protective or blocking groups for carboxyl groups are similar to those described for hydroxyl groups, preferably tert-butyl, benzyl or methyl esters.
xe2x80x9cAmino-protecting groupxe2x80x9d means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to benzyl, benzyloxycarbonyl (carbobenzyloxy; CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, and the like. It is preferred to use either BOC or CBZ as the amino-protecting group because of the relative ease of removal, for example by mild acids in the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethyl acetate; or by catalytic hydrogenation in the case of CBZ.
xe2x80x9cHydroxy-protecting groupxe2x80x9d means the protecting group that preserves a hydroxy group that otherwise would be modified by certain chemical reactions. Suitable hydroxy-protecting groups include ether-forming groups that can be removed easily after completion of all other reaction steps, such as the benzyl or the trityl group optionally substituted in their phenyl ring. Other suitable hydroxy-protecting groups include alkyl ether groups, the tetrahydropyranyl, silyl, trialkylsilyl ether groups and the allyl group.
xe2x80x9cDeprotectionxe2x80x9d or xe2x80x9cdeprotectingxe2x80x9d means the process by which a protective group is removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Deprotecting reagents for protected hydroxyl or carboxyl groups include potassium or sodium carbonates, lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts, or boron tribromide, and the like.
xe2x80x9cLeaving groupxe2x80x9d means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, benzenesulfonyloxy, tosyloxy, thiomethyl, and thienyloxy, dihalophosphinoyloxy, tetrahalophosphoxy, optionally substituted benzyloxy, isopropyloxy, mesyloxy, tosyloxy, acyloxy, and the like.
xe2x80x9cInert organic solventxe2x80x9d or xe2x80x9cinert solventxe2x80x9d means the solvent inert under the conditions of the reaction being described in conjunction therewith including, for example, benzene, toluene, acetonitrile, methyl sulfoxide (DMSO), tetrahydrofuran (THF), N,N-dimethylformamide (DMF), chloroform (CHCl3), methylene chloride or dichloromethane (CH2Cl2), dichloroethane, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents.
xe2x80x9cIsomerismxe2x80x9d means the compounds have identical molecular formulae but that differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and stereoisomers that are nonsuperimposable mirror images are termed xe2x80x9cenantiomersxe2x80x9d or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a xe2x80x9cchiral center.xe2x80x9d
xe2x80x9cChiral isomerxe2x80x9d means a compound with one chiral center. It has two enantiomeric forms of opposite chirality, and may exist as either an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a xe2x80x9cracemic mixture.xe2x80x9d A compound that has more than one chiral center has 2nxe2x88x921 enantiomeric pairs, where n is the number of chiral centers. Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a xe2x80x9cdiastereomeric mixture.xe2x80x9d
When one chiral center is present a stereoisomer may be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al. Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al. Angew. Chem. 1966, 78, 413; Cahn and Ingold J. Chem. Soc. (London) 1951, 612; Cahn et al. Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
xe2x80x9cGeometric isomersxe2x80x9d means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.
xe2x80x9cAtropic isomersxe2x80x9d means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond.
The scope of the present invention comprises compounds that possess geometric isomerism, and that may or may not possess chiral or atropic isomerism in their substituents. Such compounds can therefore be produced as mixtures of stereoisomers, or as the individual isolated or purified stereoisomers. The individual enantiomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis followed by completion of the synthesis in a way that preserves chirality, or by resolution of the compound of Formula (I) by conventional means. The individual enantiomers as well as racemic or non-racemic mixtures thereof are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.
A xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d means a carrier that is useful in preparing a pharmaceutical composition that is generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable carrierxe2x80x9d as used in the specification and claims includes both one and more than one such carrier.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable, as described herein, and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, camphorsulfonic acid, p-chlorobenzenesulfonic acid, cinnamic acid, citric acid, cyclopentanepropionic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, lauryl sulfuric acid, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, 4,4xe2x80x2-methylenebis(3-hydroxy-2-ene-1-carboxylic acid), muconic acid, 2-napthalenesulfonic acid, oxalic acid, 3-phenylpropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, trimethylacetic acid, tertiary butylacetic acid, p-toluenesulfonic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methyl-glucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, and sodium hydroxide.
The preferred pharmaceutically acceptable salts are the salts formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt
xe2x80x9cCrystal formsxe2x80x9d (or polymorphs) means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate
xe2x80x9cSolvatesxe2x80x9d means solvent additions forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H2O, such combination being able to form one or more hydrate.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, and disease state being treated, the severity of the disease state treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors.
xe2x80x9cProdrugxe2x80x9d means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve easy of formulation, or provide site-specific delivery of the compound. Reference to a compound herein includes prodrug forms of a compound.
xe2x80x9cDisease statexe2x80x9d means any disease, condition, symptom, or indication.
xe2x80x9cModulatorxe2x80x9d means a molecule, such as a compound, that interacts with a target. The interactions include, but are not limited to, agonist, antagonist, and the like, as defined herein.
xe2x80x9cAntagonistxe2x80x9d means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or receptor site.
xe2x80x9cAgonistxe2x80x9d means a molecule, such as a compound, a drug, an enzyme activator or a hormone, that enhances the activity of another molecule or receptor site.
xe2x80x9cAlpha1-adrenergic receptorsxe2x80x9d, xe2x80x9calpha1A-adrenergic receptorsxe2x80x9d (previously known as xe2x80x9calpha1C-adrenergic receptorsxe2x80x9d), xe2x80x9calpha1B-adrenergic receptorsxe2x80x9d, xe2x80x9calpha1D-adrenergic receptorsxe2x80x9d, or xe2x80x9calpha1L-adrenergic receptorsxe2x80x9d, used interchangeably with xe2x80x9calpha1-adrenoceptorsxe2x80x9d, xe2x80x9calpha1A-adrenoceptorsxe2x80x9d (previously known as xe2x80x9calpha1C-adrenoceptorsxe2x80x9d), xe2x80x9calpha1B-adrenoceptorsxe2x80x9d, xe2x80x9calpha1D-adrenoceptorsxe2x80x9d, and xe2x80x9calpha1L-adrenoceptorsxe2x80x9d, respectively, refers to a molecule conforming to the seven membrane-spanning G-protein receptors, which under physiologic conditions mediate various actions, for example, in the central and/or peripheral sympathetic nervous system through the binding of the catecholamines, epinephrine, and norepinephrine. Examples of physiological effects mediated by xe2x80x9calpha1-adrenoceptorsxe2x80x9d include, but are not limited to, control of blood pressure, glycogenolysis, growth and hypertrophy of cardiac myocytes, contractility of the urinary tract, and the like.
The term xe2x80x9calpha1-adrenergic receptor subtypexe2x80x9d used interchangeably with xe2x80x9calpha1-adrenoceptor subtypexe2x80x9d refers to a distinct member of the class of alpha1-adrenoceptors, selected from the alpha1A- (previously known as alpha1C-), alpha1B-, alpha1D- and alpha1L-adrenoceptors. The subtypes have been distinguished based on differential binding profiles of ligands, such as the agonist oxymetazoline, and such as the antagonists, WB4101 and phentolamine. Furthermore, the genes encoding the alpha1A- (previously known as alpha1C-), alpha1B- and alpha1D-subtypes have been isolated and cloned. The existence of an additional subtype, the alpha1L adrenergic receptor subtype, has been proposed; however, the gene for the alpha1L adrenergic receptor subtype has not yet been cloned.
The term xe2x80x9cspecific alpha1-adrenergic receptorxe2x80x9d as used herein, refers to a distinct member of the group or class of adrenoceptors, which may be selected from the alpha1A- (previously known as alpha1C-), alpha1B-, alpha1D- and alpha1L-adrenoceptors. Preferred species from which may be derived or isolated alpha1-adrenergic receptor subtype polypeptides, genes encoding an alpha1-adrenergic receptor subtype, and/or cells, tissues and organs that express one or more alpha1-adrenergic receptor subtype, include human, bovine, rat, murine, porcine, bovine, and the like. A more preferred species is human.
xe2x80x9cAlpha1B-adrenergic receptorsxe2x80x9d means a specific alpha1-adrenoceptor expressed in numerous tissues, most notably in the liver, heart and cerebral cortex. alpha1B-adrenoceptors are also present in areas of the spinal cord which receive input from sympathetic neurons originating in the pontine micturition center, and are presumed to be involved in the regulation of bladder function.
The term xe2x80x9cpharmacological effectxe2x80x9d as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy. In one preferred embodiment, a pharmacological effect means that pain symptoms of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the reduction of pain in a treated subject. In another preferred embodiment, a pharmacological effect means that disorders or symptoms of the urinary tract of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the prevention or reduction of incontinence or pelvic hypersensitivity in a treated subject.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease state includes:
(1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state,
(2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms, or
(3) relieving the disease state i.e., causing regression of the disease state or its clinical symptoms.
The term xe2x80x9csubjectxe2x80x9d as used herein encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non-mammals include, but are not limited to, birds and the like. The term does not denote a particular age or sex.
xe2x80x9cTraumaxe2x80x9d means any wound or injury. Trauma can produce, for example, acute and/or chronic pain, inflammatory pain, and neuropathic pain.
xe2x80x9cPainxe2x80x9d means the more or less localized sensation of discomfort, distress, or agony, resulting from the stimulation of specialized nerve endings. There are many types of pain, including, but not limited to, lightning pains, phantom pains, shooting pains, acute pain, inflammatory pain, neuropathic pain, complex regional pain, neuralgia, neuropathy, and the like (Dorland""s Illustrated Medical Dictionary, 28th Edition, W.B. Saunders Company, Philadelphia, Pa.). The goal of treatment of pain is to reduce the degree or severity of pain perceived by a treatment subject.
xe2x80x9cNeuropathic painxe2x80x9d means the pain resulting from functional disturbances and/or pathological changes as well as noninflammatory lesions in the peripheral nervous system. Examples of neuropathic pain include, but are not limited to, thermal or mechanical hyperalgesia, thermal or mechanical allodynia, diabetic pain, entrapment pain, and the like.
xe2x80x9cHyperalgesiaxe2x80x9d means the abnormally increased pain sense, such as pain that results from an excessive sensitiveness or sensitivity.
xe2x80x9cHypalgesiaxe2x80x9d (or xe2x80x9chypoalgesiaxe2x80x9d) means the decreased pain sense.
xe2x80x9cAllodyniaxe2x80x9d means the pain that results from a non-noxious stimulus to the skin. Examples of allodynia include, but are not limited to cold allodynia, tactile allodynia and the like.
xe2x80x9cComplex regional pain syndromesxe2x80x9d means the pain that includes, but is not limited to, reflex sympathetic dystrophy, causalgia, sympathetically maintained pain, and the like.
xe2x80x9cCausalgiaxe2x80x9d means the burning pain, often accompanied by trophic skin changes, due to injury of a peripheral nerve.
xe2x80x9cNociceptionxe2x80x9d means pain sense. xe2x80x9cNociceptorxe2x80x9d means a structure that mediates nociception. Nociception may be the result of a physical stimulus, such as, mechanical, electrical, thermal, or a chemical stimulus. Most nociceptors are in either the skin or the viscera walls.
xe2x80x9cAnalgesiaxe2x80x9d means the relief of pain without the loss of consciousness. An xe2x80x9canalgesicxe2x80x9d is an agent or drug useful for relieving pain, again, without the loss of consciousness.
xe2x80x9cDisorders of the urinary tractxe2x80x9d or xe2x80x9curopathyxe2x80x9d used interchangeably with xe2x80x9csymptoms of the urinary tractxe2x80x9d means the pathologic changes in the urinary tract. Symptoms of the urinary tract include overactive bladder (also known as detrusor hyperactivity), outlet obstruction, outlet insufficiency, and pelvic hypersensitivity. Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like.
xe2x80x9cOveractive bladderxe2x80x9d or xe2x80x9cDetrusor hyperactivityxe2x80x9d includes, but is not limited to, the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like.
xe2x80x9cOutlet obstructionxe2x80x9d includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors and the like. It is usually symptomatically manifested as obstructive (low flow rates, difficulty in initiating urination, and the like), and irritative (urinary urge and frequency, suprapubic pain, nocturia, and the like).
xe2x80x9cOutlet insufficiencyxe2x80x9d includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, or mixed incontinence. It is usually symptomatically manifested as stress incontinence.
xe2x80x9cPelvic Hypersensitivityxe2x80x9d includes but is not limited to pelvic pain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, and the like. It is symptomatically manifested as pain, inflammation or discomfort referred to the pelvic region, and usually includes symptoms of overactive bladder.
II. Modes of Carrying out the Invention
Before describing the present invention in detail, it is to be understood that this invention is not limited to particular formulations or process parameters as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only, and is not intended to be limiting.
Although a number of methods and materials similar or equivalent to those described herein can be used in the practice of the present invention, the preferred materials and methods are described herein.
Nomenclature
The naming and numbering of the compounds of this invention is illustrated below.
In general, the nomenclature used in this application is based on AutoNom, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature.
For example, a compound of Formula (I) 
wherein R1 is naphthyl, X is piperazinyl, and Y is xe2x80x94COxe2x80x94R4, wherein R4 is furanyl, is named:
4-[4-(Furan-2-carbonyl)-piperazin-1-ylmethylene]-2-naphthalen-1-yl-4H-oxazol-5-one.
Similarly, a compound of Formula (I) wherein R1 is benzofuranyl, X is piperazinyl, and Y is xe2x80x94R3, wherein R3 is benzimidazolyl, is named:
2-Benzofuran-4-yl-4-[4-(1H-benzoimidazol-2-yl)-piperazin-1-ylmethylene]-4H-oxazol-5-one.
Additionally, a compound of Formula (I) wherein R1 is naphthyl, X is piperazinyl, and Y is xe2x80x94COxe2x80x94NHxe2x80x94R5, wherein R5 is 3-fluorophenyl, is named:
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid (3-fluoro-phenyl)-amide.
Similarly, a compound of Formula (I) wherein R1 is benzofuranyl, X is piperazinyl, and Y is xe2x80x94C(NH)xe2x80x94NHxe2x80x94R7, wherein R7 is pyridyl, is named:
4-(2-Benzofuran-7-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine.
Preferred Compounds
Among the compounds of the present invention set forth in the Summary of the Invention, certain additional compounds are preferred. For example, preferred compounds of Formula (I), or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, include:
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid phenylamide (208, Example 13);
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (276, Example 16);
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (334, Example 19);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-naphthalen-1-yl-4H-oxazol-5-one (416, Example 24);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (212, Example 13);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (278, Example 16);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (336, Example 19);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-(4-fluoro-naphthalen-1-yl)-4H-oxazol-5-one (418, Example 24);
4-[4-(4,5-Dihydro-1H-imidazol-2-yl)-piperazin-1-ylmethylene]-2-(4-fluoro-naphthalen-1-yl)-4H-oxazol-5-one (500, Example 30);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (248, Example 14);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 324, Example 17);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 382, Example 20);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-(7-fluoro-benzofuran-4-yl)-4H-oxazol-5-one (464, Example 25);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid phenylamide (250, Example 14);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 326, Example 17);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 338, Example 20);
2-Benzofuran-4-yl-4-[4-(1H-benzoimidazol-2-yl)-piperazin-1-ylmethylene]-4H-oxazol-5-one (as hydrochloride 458, Example 25);
4-[2-(2,3-Dihydro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (254, Example 14);
4-[2-(2,3-Dihydro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 330, Example 17);
4-[2-(2,3-Dihydro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 386, Example 20);
4-(2-Benzofuran-7-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid phenylamide (252, Example 14);
1 5 4-(2-Benzofuran-7-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 318, Example 17);
4-(2-Benzofuran-7-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 332, Example 20);
2-Benzofuran-7-yl-4-[4-(4,5-dihydro-1H-imidazol-2-yl)-piperazin-1-ylmethylene]-4H-oxazol-5-one (as hydrochloride 498, Example 30);
4-[2-(2,3-Dihydro-benzofuran-7-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (242, Example 14);
4-[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (256, Example 14);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-4H-oxazol-5-one (466, Example 25); and
2-(2,3-Dihydro-benzo[1,4]dioxin-5-yl)-4-[4-(4,5-dihydro-1H-imidazol-2-yl)-piperazin-1-ylmethylene]-4H-oxazol-5-one (504, Example 30).
More preferred compounds of Formula (I), or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, include:
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid phenylamide (208, Example 13);
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (276, Example 16);
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (334, Example 19);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-naphthalen-1-yl-4H-oxazol-5-one (416, Example 24);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (212, Example 13);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (278, Example 16);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (336, Example 19);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-(4-fluoro-naphthalen-1-yl)-4H-oxazol-5-one (418, Example 24);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-piperazine-1-carboxylic acid phenylamide (248, Example 14);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 324, Example 17);
4-[2-(7-Fluoro-benzofuran-4-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 382, Example 20);
4-[4-(1H-Benzoimidazol-2-yl)-piperazin-1-ylmethylene]-2-(7-fluoro-benzofuran-4-yl)-4H-oxazol-5-one (464, Example 25);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-piperazine-1-carboxylic acid phenylamide (250, Example 14);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 326, Example 17);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 338, Example 20); and
2-Benzofuran-4-yl-4-[4-(1H-benzoimidazol-2-yl)-piperazin-1-ylmethylene]-4H-oxazol-5-one (as hydrochloride 458, Example 25).
Even more preferred compounds of Formula (I), wherein the compound is present as an individual isomer, a racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or solvate thereof, include:
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (276, Example 16);
4-(2-Naphthalen-1-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (334, Example 19);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-pyridin-2-yl-piperazine-1-carboxamidine (278, Example 16);
4-[2-(4-Fluoro-naphthalen-1-yl)-5-oxo-oxazol-4-ylidenemethyl]-N-phenyl-piperazine-1-carboxamidine (336, Example 19);
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-pyridin-2-yl-piperazine-1-carboxamidine (as hydrochloride 326, Example 17); and
4-(2-Benzofuran-4-yl-5-oxo-oxazol-4-ylidenemethyl)-N-phenyl-piperazine-1-carboxamidine (as hydrochloride 338, Example 20).
Another preferred group includes the pharmaceutically acceptable salts or solvates of the compounds of the present invention wherein the pharmaceutically acceptable salts are formed from acetic acid, hydrochloric acid, sulphuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc, and magnesium.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Wiley and Sons, New York, 1991, Volumes 1-15; Rodd""s Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic Reactions, Wiley and Sons, New York, 1991, Volumes 1-40. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range from about xe2x88x9278xc2x0 C. to about 150xc2x0 C., more preferably from about 0xc2x0 C. to about 125xc2x0 C.
Compounds of Formula (I) are prepared using general methods described in the literature. Particularly, intermediate compounds of structure 3 in which R1 is as described herein can be prepared as described in, for example, Cornforth, J. W., The Chemistry of Penicillin, Princeton University Press, Princeton N.J., 1949, Chapter 21; Bland J. M. et al., Journal of Organic Chemistry, 1984, 49, 1634-1636 and Kocevar M. et al., Liebigs Ann. Chem., 1990, 5, 501-503.
Generally, as set forth in reaction Scheme 1, a carboxylic acid 1 is first converted to the corresponding acid chloride, by treatment with, for example, oxalyl chloride, followed by conversion to the corresponding glycine amide 2. The resulting acid-amide 2 can be cyclized using, for example, triethyl orthoformate and acetic anhydride at 80xc2x0 C. to yield the R1-substituted 4-ethoxymethylene-5-oxazolones 3. 
In general, the compounds of the present invention can be prepared by first alkylating an optionally substituted amine, such as 4A, 4B or 4C (wherein Y is as described above; see reaction Scheme 2) with an R1-substituted 4-ethoxy-methylene-5-oxazolone 3 (prepared as set forth in reaction Scheme 1), to yield compounds 5A, 5B or 5C, respectively. 
An alternative method of preparing the compounds of this invention is alkylation of a suitably mono-protected diamine, such as 6A, 6B or 6C, with an R1-substituted 4-ethoxymethylene-5-oxazolone 3 (prepared as set forth in reaction Scheme 1), to yield compounds 7A, 7B or 7C (wherein P denotes a suitable protecting group as described herein, such as benzyl, benzyloxycarbonyl (carbobenzyloxy; CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), trifluoroacetyl, preferably BOC or CBZ), and then deprotecting (see reaction Scheme 3), to yield compounds 8A, 8B or 8C. Compounds 5A, 5B and 5C can be then prepared by adding an appropriately activated Y, wherein Y is as defined herein, onto compounds 8A, 8B or 8C, respectively.
The alkylation of compounds 6A, 6B or 6C can be carried out neat at about 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C., requiring about 1 to about 24 hours (for further details see, e.g., Example 2, infra). Alternatively, the reaction can be carried out in a suitable inert organic solvent (e.g., acetonitrile, methyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidione (NMP), benzene, toluene, any appropriate mixture of suitable solvents, etc., preferably acetonitrile or DMSO) with a suitable base present (e.g., sodium carbonate, potassium carbonate, cesium carbonate, 2,4,6-trimethylpyridine, triethylamine, N,N-diisopropylethylamine, etc., preferably sodium carbonate, triethylamine, or N,N-diisopropylethylamine) at 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C., and preferably at reflux, requiring about 2 to about 72 hours (for further details see, e.g., Example 3, infra).
Deprotection of compounds 7A, 7B or 7C, in which a nitrogen protective group is present, can be effected by any means which remove the protective group and give the desired product 8A, 8B or 8C. As described herein, a detailed description of the techniques applicable to protective groups and their removal can be found in T. W. Greene, Protective Groups in Organic Synthesis, Wiley and Sons, New York, 1991. For example, a convenient method of deprotection when the protective group is N-tert-butoxycarbonyl can be carried out with trifluoroacetic acid or hydrochloric acid in a suitable inert organic (e.g., ethyl acetate, dichloromethane, tetrahydrofuran (THF), hexamethylphosphoramide (HMPA), or any appropriate mixture of suitable solvents, etc., preferably THF or ethyl acetate) at 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C., and requires about 8 to about 24 hours (for further details see, e.g., Example 3, infra). Deprotection, when the protective group is benzyl or CBZ, can be carried out by catalytic hydrogenation. The hydrogenation is carried out with a suitable catalyst (e.g., 10% palladium on carbon (10% Pd/C), palladium hydroxide, palladium acetate, etc. preferably 10% Pd/C) in the presence of ammonium formate and in an appropriate solvent, typically an alcohol (e.g., ethanol, methanol, isopropanol, any appropriate mixture of alcohols, etc.), preferably methanol, at about 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C. and preferably at reflux. Alternatively, the benzyl group can be removed by treating the protected compound with the catalyst under a hydrogen atmosphere at 0 to 50 psi, typically at 10 to 20 psi and preferably at approximately 15 psi, at about 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C., and preferably at about 20xc2x0 to about 100xc2x0 C.
Compounds 5A, 5B and 5C can then prepared by adding an appropriately activated Y, wherein Y is as defined herein, onto compounds 8A, 8B or 8C, respectively. The substitution reaction is carried out at about 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C., requiring about 1 to about 24 hours. The reaction can be carried out in a suitable inert organic solvent (e.g., acetonitrile, methyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N-methylpyrrolidione (NMP), benzene, toluene, any appropriate mixture of suitable solvents, etc., preferably acetonitrile or DMSO) with a suitable base optionally present , e.g., sodium carbonate, potassium carbonate, cesium carbonate, 2,4,6-trimethylpyridine, triethylamine, N,N-diisopropylethylamine (Hxc3xcnig""s base), etc., preferably sodium carbonate, triethylamine, N,N-diisopropylethylamine (Hxc3xcnig""s base); for further details see, e.g., Examples 4, 5, 6 and 7, infra at about 0xc2x0 to about 250xc2x0 C., typically at about 10xc2x0 to about 150xc2x0 C. and preferably at about 20xc2x0 to about 100xc2x0 C. and more preferably at reflux, requiring 2 to 72 hours, see, e.g., Example 5, infra. 
Administration and Pharmaceutical Compositions
The invention provides pharmaceutical compositions comprising a compound of the present invention or a pharmaceutically acceptable salt, solvate or derivative thereof together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. Suitable dosage ranges are about 1 mg to about 500 mg daily, preferably about 1 mg to about 100 mg daily, and more preferably about 1 mg to about 30 mg daily, depending upon numerous factors such as the severity of the disease state to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical or veterinary practitioner involved. One of ordinary skill in the art of treating such a disease state will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for use in treating a given disease state.
In general, compounds of this invention will be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous, and intravenous) administration or in a form suitable for administration by inhalation or insufflation. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
The compounds of the invention, together with a conventional adjuvant, carrier, or diluent, may be placed into the form of pharmaceutical compositions and unit dosages. The pharmaceutical compositions and unit dosage forms may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed. The pharmaceutical composition may be employed as solids, such as tablets or filled capsules, semisolids, powders, sustained release formulations, or liquids such as solutions, suspensions, emulsions, elixirs, or filled capsules for oral use; or in the form of suppositories for rectal or vaginal administration; or in the form of sterile injectable solutions for parenteral use. Formulations containing about 0.01 to 100 milligrams, preferably 1 to 50 milligrams, more preferably 1 to 10 milligrams, per tablet, are accordingly suitable representative unit dosage forms.
The compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise the compounds of the invention or its pharmaceutically acceptable salt or solvate as the active component. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. In powders, the carrier is a finely divided solid which is a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from one to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term xe2x80x9cpreparationxe2x80x9d is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral administration.
Other forms suitable for oral administration include liquid form preparations such as emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, or solid form preparations which are intended to be converted shortly before use to liquid form preparations. Emulsions may be prepared in solutions in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents. Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
The compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or nonaqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
The compounds of the present invention may be formulated for topical administration to the epidermis as ointments, creams or lotions, or as a transdermal patch. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Formulations suitable for topical administration in the mouth include lozenges comprising active agents in a flavored base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
The compounds of the present invention may be formulated for administration as suppositories. A low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active component is dispersed homogeneously, for example, by stirring. The molten homogeneous mixture is then poured into conveniently sized molds, allowed to cool, and to solidify.
The compounds of the present invention may be formulated for vaginal administration. Pessaries, tampons, creams, gels, pastes, foams or sprays, may contain agents in addition to the active ingredient, such carriers, known in the art to be appropriate.
The compounds of the present invention may be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray. The formulations may be provided in a single or multidose form. In the case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomizing spray pump.
The compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract including intranasal administration. The compound will generally have a small particle size for example of the order of about 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form for example in capsules or cartridges of, e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
When desired, formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
Other suitable pharmaceutical carriers and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa. Representative pharmaceutical formulations containing a compound of the present invention are described in Example 49.
Pharmacology and Utility
Alpha1-adrenoceptors mediate the contractile state of smooth muscle tissue and are present in the human prostate, bladder neck and urethra. Sympathetic activity produces contraction of vascular smooth muscle which leads to elevated blood pressures. Alpha1-adrenoceptor stimulation also produces glycogenolysis, growth and hypertrophy of cardiac myocytes and contraction of urethral and bladder neck smooth muscle, leading to increased resistance in urinary outflow. Thus, alpha1-adrenoceptor antagonists may be useful in preventing hypertension and treating disorders or symptoms related to uropathies, such as obstruction due to benign prostatic hyperplasia (BPH). (See U.S. Pat. No. 5,859,014; Lepor, H., The Prostate Supplement, 1990, 3:75-84 and International Publication No. WO 95/25726.)
Some drugs effective in the treatment of benign prostatic hyperplasia block alpha1A-adrenergic mediated contractions of the prostate. Alpha1A-adrenoceptors may mediate smooth muscle hyperplasia in the prostate, therefore a selective alpha1A-adrenoceptor antagonist may have utility not only in mitigating the excessive prostatic constriction, but also in preventing progression of tissue hyperplasia.
Experimental evidence supports a therapeutic role for alpha1-adrenoceptor antagonists in treating prostatic hyperplasia. (See for example, Lepor, H., The Prostate Supplement, 1990, 3, 75-84.) Obstruction of the urinary tract can occur as a result of prostatic hyperplasia and excessive prostatic constriction of the urethra. This in turn leads to diminished urinary flow rates and an increased urgency and frequency of urination.
In a preferred embodiment, the compounds of this invention are useful for treating disease states which can be ameliorated by modulation, preferably by blockade of alpha1-adrenoceptors, such as reduction or alleviation of urinary tract disorders, for example, pelvic hypersensitivity (including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like), overactive bladder, urinary frequency, nocturia, urinary urgency, detrusor hyperreflexia, outlet obstruction, prostatitis, urge incontinence, urethritis, idiophatic bladder hypersensitivity, and the like. Compounds of this invention may also be useful for treating male erectile dysfunction and female sexual dysfunction.
In a more preferred embodiment, the compounds of the invention are useful for treating disease states which can be ameliorated by blockade of alpha1-adrenoceptors. Alpha1B-adrenoceptors are present in the liver, heart and cerebral cortex and are believed to be involved in mediating vascular contractile and blood pressure responses. Additionally, alpha1B-adrenoceptors are also present in areas of the spinal cord which receive input from sympathetic neurons originating in the pontine micturition center and are presumed to be involved in the regulation of bladder function. Selective blockade of the alpha1B-adrenoceptor may lead to the symptomatic treatment of pelvic hypersensitivity including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like, and symptoms associated with overactive bladder.
Several clinical observations suggest a therapeutic role for alpha1B-adrenoceptor antagonists in the prevention of disease states of the urinary tract, such as pelvic hypersensitivity (including interstitial cystitis, prostatitis, pelvic pain syndrome, infectious cystitis, prostatodynia, and the like), urethritis, overactive bladder (manifested as urge incontinence), detrusor hyperreflexia, outlet obstruction (resulting from benign prostatic hypertrophy and prostatitis), and other conditions of idiopathic bladder hypersensitivity.
Additionally, alpha1B-adrenoceptor antagonists are useful as analgesic/antihyperalgesic therapies for treating pain, including symptoms of acute pain, inflammatory pain, neuropathic pain (including thermal and mechanical hyperalgesia as well as thermal and mechanical allodynia), complex regional pain syndromes (including reflex sympathetic dystrophy, causalgia and sympathetically maintained pain). (See, commonly owned U.S. patent application Ser. No. 60/124,721 by Ford et al. entitled xe2x80x9cA Method For Screening Compounds For Alpha1BAdrenergic Receptor Antagonist and Analgesic Activity,xe2x80x9d filed on Mar. 17, 1999, the disclosure of which is hereby incorporated by reference in its entirety.)
Assays
The pharmacology of the compounds of this invention was determined by art-recognized procedures. In vitro techniques for determining the affinities of test compounds in radioligand binding and functional assays are described in Example 45.
The effect of the compounds of this invention on blood pressure can be evaluated by any method known in the art. Examples of such methods are as follows.
Rat In Vivo, Blood Pressure Assay
An in vivo assay for measuring the blood pressure lowering effects of test compounds in normotensive rats is described in Example 46.
Normotensive rats (0.25 to 0.45 kg) are fasted for 18 hours and anesthetized with ether. The right femoral vein is isolated and cannulated with a fluid-filled polyethylene cannulae for bolus administration of test substances. The right femoral artery is isolated and cannulated with a fluid-filled polyethylene cannula connected to an external pressure transducer for monitoring mean arterial blood pressure (MAP).
Following cannulation, rats are pretreated (intravenous route) with an angiotensin receptor antagonist, a xcex2-adrenergic receptor antagonist and an alpha2adrenergic receptor antagonist as described in Blue et al. (Br. J. Pharmacol. 120:107P).
The rats are placed in restrainers and allowed to recover from anesthesia. Following a 30-minute period for stabilization, test compound or vehicle are administered, i.v., and blood pressure is monitored continuously for at least 4 hours post-administration.
Rat In Vivo, Tilt-Response Assay
The following describes an in vivo assay in normotensive rats for measuring the propensity of a test compound to inhibit the reflex maintenance of basal blood pressure levels in response to vertical tilt.
Normotensive rats (0.25 to 0.45 kg) are fasted for 18 hours and anesthetized with ether. The right femoral vein is isolated and cannulated with a fluid-filled polyethylene cannulae for bolus administration of test substances. The right femoral artery is isolated and cannulated with a fluid-filled polyethylene cannula connected to an external pressure transducer for monitoring mean arterial blood pressure (MAP).
The rats are restrained in a supine position and allowed to recover from anesthesia. Following a 30-minute period for stabilization, test compound or vehicle are administered, i.v., and blood pressure is monitored continuously while the rats are tilted vertically at 30 to 60 degrees from supine at 15, 30 and 45 minutes post-administration.
Dog In Vivo, Blood and Intraurethral Pressure Assay
The following describes an in vivo assay for measuring the relative effect of a test compound on hypogastric nerve stimulation-induced increases in intraurethral pressure and phenylephrine-induced increases in diastolic blood pressure in anesthetized dog.
Mongrel dogs (10 to 20 kg) are fasted for 12 to 18 hours and anesthetized with phenobarbital sodium (35 mg/kg, i.v.). An endotracheal tube is inserted and thereafter the lungs are mechanically ventilated with room air. The right femoral vein is isolated and cannulated with two polyethylene cannulae, one for the administration of a continuous infusion of phenobarbital sodium (5 to 10 mg/kg/hr) and the other for bolus administration of test substances. The right femoral artery is isolated and cannulated to the abdominal aorta with a fluid filled polyethylene cannula connected to an external pressure transducer for monitoring diastolic aortic pressure (DAP). The bladder is exposed via a ventral midline abdominal incision and emptied of urine through a 22-gauge needle. The bladder is cannulated through a stab incision with a water-filled balloon catheter connected to an external pressure transducer for monitoring prostatic intraurethral pressure (IUP). The right hypogastric nerve (HGN) is carefully isolated and attached to a Dastre""s electrode for nerve stimulation.
The preparation is allowed to stabilize for a least 30 minutes and must have a stable basal IUP for not less than 15 minutes prior to commencement of the assay protocol. The HGN is stimulated (20-50 V, 10 Hz, 10 msec pulse train for 10 sec) to induce a measurable increase in IUP and then phenylephrine (PE) is administered by bolus injection (0.5 to 0.6 xcexcg/kg, i. v.) to induce a measurable increase in DAP. The HGN stimulation and PE bolus injection are repeated every 5 minutes until three consecutive reproducible increases in IUP and DAP are achieved. Vehicle (0.1 to 0.3 mL/kg) is administered and 20 minutes later the HGN stimulation and PE bolus injection are repeated. Test compound is then administered and 20 minutes later the HGN stimulation and PE bolus injection are repeated. Test compound is administered approximately every 20 minutes, increasing the dose until maximal or near maximal inhibition of the increases in IUP and DAP is attained.
The analgesic activity of the compounds of this invention can be evaluated by any method known in the art. Examples of such methods are as follows.
Tail Flick Model
The tail-flick test (D""Amour et al. (1941) J. Pharmacol. Exp. and Ther. 72:74-79) is a model of acute pain. A towel-wrapped rat is placed on a test stage such that a focused light source beams on the dorsal surface of the rat""s tail. A photosensor is present on the test stage located opposite the light source and below the rat""s tail. To begin the test the rat""s tail blocks the light, thus preventing the light reaching the photosensor. Latency measurement begins with the activation of the light source. When a rat moves or flicks its tail the photosensor detects the light source and stops the measurement. The test measures the period of time (duration) that the rat""s tail remains immobile (latent). Rats are tested pre-dose and then tested at various times post-dose. The light source is set to an intensity that produced a tail response latency of about 3 seconds when applied to the tails of pre-dose rats.
Rat Tail Immersion Model
The rat tail immersion assay is also a model of acute pain. A rat is loosely held in hand while covered with a small folded thin cotton towel with its tail exposed. The tip of the tail is dipped into a, e.g., 52xc2x0 C. water bath to a depth of two inches. The rat responds by either wiggling of the tail or withdrawal of the tail from the water; either response is scored as the behavioral end-point. A rat is tested for a pre-dose tail response latency (TRL) score. It is then dosed with a selected agent and, following dosing, retested for tail response latency at various times post-dosing.
Carrageenan-induced Paw Hyperalgesia Model
The carrageenan paw hyperalgesia test is a model of inflammatory pain. A subcutaneous injection of carrageenan is made into the left hindpaws of rats. The mammals are dosed with a selected agent before, e.g., 30 minutes, the carrageenan injection or after, e.g., two hours, the carrageenan injection. Paw pressure sensitivity for each animal is tested with an analgesymeter three hours after the carrageenan injection. See, Randall et al., Arch. Int. Pharmacodyn., 1957, 111:409-419.
The effects of selected agents on carrageenan-induced paw edema can also be examined. This test (see, Vinegar et al., J. Phamacol. Exp. Ther., 1969, 166:96-103) allows an assessment of the ability of a compound to reverse or prevent the formation of edema evoked by paw carrageenan injection. The paw edema test is carried out using a plethysmometer for paw measurements. After administration of a drug, a carrageenan solution is injected subcutaneously into the lateral foot pad on the plantar surface of the left hind paw. At three hours post-carrageenan treatment, the volume of the treated paw (left) and the un-treated paw (right) is measured using a plethysmometer.
Formalin Behavioral Response Model
The formalin test is a model of acute, persistent pain. Response to formalin treatment is biphasic (Dubuisson et al., Pain, 1977, 4:161-174). The Phase 1 response is indicative of a pure nociceptive response to the irritant. Phase 2, typically beginning 20 to 60 minutes following injection of formalin, is thought to reflect increased sensitization of the spinal cord.
Von Frey Filament Test
The effect of alpha1B-adrenergic receptor antagonists on mechanical allodynia can be determined by the von Frey filament test in rats with a tight ligation of the L-5 spinal nerve: a model of painful peripheral neuropathy. The surgical procedure is performed as described by Kim et al., Pain, 1992, 50:355-363. A calibrated series of von Frey filaments are used to assess mechanical allodynia (Chaplan et al., J. Neurosci. Methods, 1994, 53:55-63). Filaments of increasing stiffness are applied perpendicular to the midplantar surface in the sciatic nerve distribution of the left hindpaw. The filaments are slowly depressed until bending occurred and are then held for 4-6 seconds. The filament application order and number of trials were determined by the up-down method of Dixon (Chaplan et al., supra). Flinching and licking of the paw and paw withdrawal on the ligated side are considered positive responses.
Chronic Constriction Injury
Heat and cold allodynia responses can be evaluated as described below in rats having a chronic constriction injury (CCI). A unilateral mononeuropathy is produced in rats using the chronic constriction injury model described in Bennett et al., Pain, 1988, 33:87-107.
CCI is produced in anesthetized rats as follows. The lateral aspect of each rat""s hind limb is shaved and scrubbed with Nolvasan. Using aseptic techniques, an incision is made on the lateral aspect of the hind limb at the mid-thigh level. The biceps femoris is bluntly dissected to expose the sciatic nerve. On the right hind limb of each rat, four loosely tied ligatures (for example, Chromic gut 4.0; Ethicon, Johnson and Johnson, Somerville, N.J.) are made around the sciatic nerve approximately 1-2 mm apart. On the left side of each rat, an identical dissection is performed except that the sciatic nerve is not ligated (sham). The muscle is closed with a continuous suture pattern with, e.g., 4-0 Vicryl (Johnson and Johnson, Somerville, N.J.) and the overlying skin is closed with wound clips. The rats are ear-tagged for identification purposes and returned to animal housing.
Radiant Heat Model
An in vivo assay for measuring the pain response to radiant heat in neuropathic rats is described in Example 47. Generally, CCI rats are tested for thermal hyperalgesia at least 10 days post-op. The test apparatus consists of an elevated heated (80-82xc2x0 F.) glass platform. Eight rats at a time, representing all testing groups, are confined individually in inverted plastic cages on the glass floor of the platform at least 15 minutes before testing. A radiant heat source placed underneath the glass is aimed at the plantar hind paw of each rat. The application of heat is continued until the paw is withdrawn (withdrawal latency) or the time elapsed is 20 seconds. This trial is also applied to the sham operated leg. Two to four trials are conducted on each paw, alternately, with at least 5 minutes interval between trials. The average of these values represents the withdrawal latency.
Cold Allodynia Model
The test apparatus and methods of behavioral testing is described in Ford et al., Analgesia, 1997, 3:111-118. An in vivo assay for measuring the pain response to cold allodynia model in neuropathic rats is described in Example 48.
The apparatus for testing cold allodynia in neuropathic (CCI) rats consists of a Plexiglass chamber with a metal plate 6 cm from the bottom of the chamber. The chamber is filled with ice and water to a depth of 2.5 cm above the metal plate, with the temperature of the bath maintained at 0-4xc2x0 C. throughout the test.
Each rat is placed into the chamber individually, a timer started, and the animal""s response latency was measured to the nearest tenth of a second. A xe2x80x9cresponsexe2x80x9d is defined as a rapid withdrawal of the right ligated hindpaw completely out of the water what the animal is stationary and not pivoting. An exaggerated limp while the animal is walking and turning is not scored as a response. The animals"" baseline scores for withdrawal of the ligated leg from the water typically range from 7-13 seconds. The maximum immersion time is 20 seconds with a 20-minute interval between trials.
Preferred compounds of this invention demonstrate selectivity for the alpha1B-adrenoceptor subtype over the alpha1A- and alpha1D-adrenoceptor subtypes. In contrast to non-subtype-selective alpha1-adrenoceptor antagonists, the alpha1B-adrenoceptor selective antagonist compounds of this invention do not demonstrate any significant cardiovascular effects in vivo at therapeutically effective doses. The compounds of this invention can selectively reduce or alleviate urinary tract disorders or symptoms, or ameliorate nociceptive and/or neurogenic pain, without producing the blood pressure lowering effects and/or the postural hypotension that are associated with previously described alpha1-adrenoceptor antagonists.